Identifying drug-drug interactions

Adverse events caused by drug-drug interactions are a growing problem in hospital medicine.
Such interactions harm anywhere from 1.9 to 5 million inpatients per year, according
to data from the CDC. The problem is likely to grow in the future as the population
ages and more people take multiple medications.

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Experts say that the conventional methods of detecting drug-drug interactions, such
as adverse drug event reports from clinicians and patients and preclinical toxicity
studies, can't uncover all the potentially clinically relevant interactions. As a
result, dangerous interactions sometimes aren't identified until a drug has been on
the market for many years.

“There may be many potentially important DDIs [drug-drug interactions] that
we've not yet identified,” said Sean Hennessy, PharmD, PhD, professor of epidemiology
and systems pharmacology and translational therapeutics at the Perelman School of
Medicine at the University of Pennsylvania in Philadelphia. “We need to increase
the amount of reliable research on DDIs and improve the translation of that research.”

Researchers are making some progress in developing new ways to detect potentially
harmful drug-drug interactions and alert prescribers about them. For example, a study
published in the Oct. 18, 2016, Journal of the American College of Cardiology highlighted a promising new approach that combined data mining and laboratory experiments.

Using an algorithm known as latent signal detection, researchers scanned 1.8 million
adverse event reports from the FDA's Adverse Event Reporting System and 1.6 million
electrocardiograms from New York-Presbyterian/Columbia University Medical Center and
identified eight pairs of drugs that may be associated with a greater risk of acquired
long QT syndrome. Next, they evaluated the effect of two of the drugs—the antibiotic
ceftriaxone and the proton-pump inhibitor lansoprazole—alone and in combination,
using electrophysiological experiments on individual cells in the lab.

They focused on this combination because lansoprazole is such a commonly prescribed
drug and an interaction could have a profound impact on patient safety, as well as
because the effects were among the most statistically significant of all those identified.
This interaction is also most likely to occur in hospitalized patients, since many
could already be taking lansoprazole and then could be prescribed ceftriaxone when
they're admitted for surgery, noted study author Nicholas Tatonetti, PhD, assistant
professor of biomedical informatics at Columbia University Medical Center.

Results showed that patients taking ceftriaxone and lansoprazole together were 40%
more likely to have a QT interval above 500 ms, which is the FDA-stated threshold
of clinical concern. When taken together, these widely prescribed drugs block an electrical
pathway in the cell called the hERG channel, which helps coordinate the beating of
the heart.

“Our method allows us to identify adverse reactions that result from combination
therapy no one would have suspected otherwise,” Dr. Tatonetti said. “We
can identify a novel hypothesis, corroborate it with an additional data set, and then
validate it with experiments.”

His team is currently testing more of the potentially QT-prolonging drug combinations
they identified on cells in the lab and using their approach to investigate potential
interactions involving beta-blockers and other classes of drugs.

Follow-up confirmation studies are needed before physicians are advised to avoid prescribing
ceftriaxone and lansoprazole together, according to the authors of the study and other
drug safety researchers.

“While these results are very important, I wouldn't want someone to overextrapolate
from these data. For example, we don't yet know if the same interaction will be found
with other proton-pump inhibitors and ceftriaxone,” said Raymond L. Woosley,
MD, PhD, FACP, professor of biomedical informatics and medicine at the University
of Arizona College of Medicine-Phoenix; president of AZCERT, a nonprofit focused on
drug safety; and a coauthor of the study.

Dr. Tatonetti and colleagues are currently studying the effects of the drugs individually
and in combination on the QT interval in patients already undergoing inpatient electrophysiology
studies.

Over the past several years, a number of other research teams around the world have
started to leverage data from electronic health records (EHRs), adverse event reporting
systems such as the FDA database and the World Health Organization's VigiBase, insurance
claim databases, and published literature to identify possible interactions.

“The hope is that with new data-mining techniques and the increasing availability
of large clinical databases such as EHRs, we can pick up DDIs much more quickly than
in the past and prioritize the ones that are important for further study, in particular,
to measure their medical impact and means of prevention,” said Dr. Woosley.

Predicting DDIs in individuals

Another promising investigative approach focuses on predicting potential drug-drug
interactions in individual patients. Joseph C. Wu, MD, PhD, director of the Stanford
Cardiovascular Institute in California, is developing a method of using induced pluripotent
stem cells to determine whether a specific drug or drug-drug interaction is likely
to cause damage to an individual patient's heart.

The technique involves taking a patient's blood sample, converting the blood cells
to the pluripotent stem cells, and then converting those to heart muscle cells (cardiomyocytes).

These beating heart cells are genetically identical to those of the patient. The researchers
then expose the cells to one or more medications and measure the effects on the heart,
for instance, whether the medications cause the heart cells to die or to beat irregularly.

This type of testing can help determine which potentially beneficial medication would
be safest for a patient. It might also help confirm if a drug-drug interaction is
currently taking place in a patient. For example, if a patient with an arrhythmia
is on five medications and an interaction is suspected, the testing could be used
to find out which of the drugs is causing the problem.

“This platform allows us to test drug-drug interactions in patient-specific
and disease-specific human heart cells. The patient doesn't have to be the guinea
pig,” said Dr. Wu, who is also a professor of medicine and radiology at Stanford
University School of Medicine.

Other scientists are generating kidney, brain, liver, and endothelial cells from induced
pluripotent stem cells for drug screening applications. Dr. Wu predicts that within
the next five years, a version of this technology will be available for commercial
use.

Improving tools for prescribers

For hospitalists and other physicians who are trying to prevent drug-drug interactions
in everyday practice, the biggest immediate challenge may be that the existing clinical
decision support tools aren't useful enough.

Currently, most computerized provider order entry (CPOE) systems include interruptive
alerts that notify prescribers of potential drug-drug and drug-allergy interactions.
Since the drug information databases that power these alerts are created and sold
by a variety of different companies, there is limited agreement between them.

Physicians and pharmacists typically override about 90% of the alerts, according to
numerous studies, since they don't find them to be relevant enough to specific patients
and because the alerts interrupt workflow.

“Physicians should be able to rely on the DDI information systems, and right
now those systems are failing them,” said Dr. Hennessy. “It's almost
certainly true that many of the potential DDIs that we currently send prescribers
alerts for aren't clinically important in most patients.”

Many in the drug safety community believe that CPOE systems should ideally provide
more specific information about whether an interaction could occur in the patient
for which the prescription is being ordered. “What doctors and pharmacists
want to know is: Is the DDI likely to cause harm to this specific patient because
of their risk profile?” said Dr. Woosley.

Along with collaborators at Banner Health and the University of Arizona College of
Medicine-Phoenix and support from the FDA's Safe Use Initiative, he is developing
a clinical decision support tool that helps physicians evaluate the risk for torsade
de pointes from commonly used antibiotics such as levofloxacin, erythromycin, clarithromycin,
and azithromycin.

Running in the background as part of the EHR, the program takes data from the patient's
records and calculates a score to estimate risk, looking at such factors as whether
the patient is already taking potentially QT-prolonging medications or has sepsis
or bradycardia.

When a physician prescribes an antibiotic with a known risk of prolonging the QT interval
to a patient with a high risk score, the program issues an advisory and suggests alternative
medications or other strategies, such as monitoring the patient's electrocardiogram
for excessive QT prolongation or correcting the patient's potassium level if it's
low.

The 20 ICUs in the Banner Health system recently adopted this clinical decision support
tool, which is based on similar ones that were developed by investigators at Indiana
University in Indianapolis and at Mayo Clinic in Rochester, Minn. Dr. Woosley and
his colleagues plan to evaluate its effectiveness and continually update it to address
changes in medical practice, such as the release of new drugs or the identification
of new risk factors.

“This model is the future,” said Dr. Woosley. “Just as airlines
use autopilot systems to assist pilots in managing data and making decisions, CPOE
systems could provide physicians with the information they need to make optimal decisions
about DDIs for individual patients and not make mistakes.”

Jennifer Uscher is a freelance writer in Brooklyn, N.Y.

Guideline Corner: Interactions between statins, heart meds

The American Heart Association released a scientific statement recently offering guidance
on managing clinically significant drug-drug interactions for statins and cardiovascular
medications.

The statement provides an overview of drug-drug interactions and the pharmacological
differences among various statins, describes how they relate to certain medications
used to treat patients who have cardiovascular disease, and offers recommendations
on clinical management. Recommendations were based on data from clinical trials, case
reports, prescribing information, and pharmacokinetic studies.

The recommendations cover drug-drug interactions between statins and each of the following:
fibrates, calcium-channel blockers, antiarrhythmic agents, ranolazine, warfarin, ticagrelor,
conivaptan, vasopressin-receptor antagonists, immunosuppressive agents, colchicine,
and heart failure medications. Tables are provided summarizing the evidence for and
magnitude of drug-drug interactions with statins as well as recommendations for management.

For example, the statement recommends that in patients taking amlodipine combined
with simvastatin or lovastatin, the dosage of either statin should not exceed 20 mg/d,
and for patients in whom statin-fibrate therapy is indicated, fenofibrate or fenofibric
acid is preferred because of a lower rate of drug-drug interactions. The writing committee
noted that it is often impossible to avoid drug interactions with statins in cardiovascular
patients, making appropriate clinical management essential, and stressed that clinicians
must have thorough knowledge of the pharmacokinetics of both statins and medications
often prescribed with them in combination.

In addition, the committee wrote, “A review of all medications that statin-treated
patients are taking should be done at each clinical encounter and during transitions
of care within a health system so that [drug-drug interactions] can be identified
early, evaluated, and managed appropriately by implementing doses adjustments, changing
to a safer statin medication, or discontinuing when needed.”

The statement was published online Oct. 17, 2016, by Circulation and appeared in the Feb. 17, 2017, issue.

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